The benzo[c]phenanthridinium alkaloids are a class of naturally occurring pharmaceutically active compounds that have been known for centuries. Well-known benzo[c]phenathridinium alkaloids include sanguinarine, chelerythrine, nitidine, and fagaronine.
Pharmaceutical utility for several of the benzo[c]phenantridinium alkaloids has been demonstrated. Sanguinarine and chelerythrine possess protein kinase C(PKC) antagonist activity, anti-microbial activity, and anti-fungal properties. These compounds are the major constituents of an extract used to treat gum disease and reduce plaque. Sanguinaria extract (containing approx. 50% sanguinarine and 25% chelerythrine) has been utilized in a commercial dental rinse and toothpaste. Nitidine and fagaronine have anti-cancer activity and have been investigated in clinical trials. Cardiovascular toxicity has limited the development of Nitidine as an anti-cancer drug.
Generally, phenanthridinium alkaloids have strong cytotoxic activity and are active topisomerase I, and/or topoisomerase II inhibitors as well as modulators of a number of other receptors and enzymes, particularly protein kinases. Chelerythrine does not stabilize the DNA adduct as do the others in this class.
The benzo[c]phenanthridinium alkaloids all possess a common phenathridine core and additionally have in common a quartenary nitrogen. The quartenary nitrogen and molecular planarity are postulated to be responsible for the rich pharmacology associated with these alkaloids as reduction to the dihydro analog results in a significant reduction of pharmacological activities.
The quaternary nitrogen imparts inherent chemical reactivity into these alkaloids. Nucleophiles can readily add to the adjacent carbon to create a neutral pseudobase. Water forms an unstable adduct with chelerythrine that can be seen in NMR studies. Additionally, 6-methoxy-5,6-dihydrochelerytherine and 6-ethoxy-5,6-dihydrochelerytherine (Artarine) have been reported as byproducts formed during the isolation of chelerythrine from plants utilizing methanol and ethanol extractions. The ability of this class of compounds to form pseudobases which can convert back to the quartenary carbon is dependent on the solubility of the resulting pseudobase in biological media, the basicity of the leaving group adjacent to the position to become quartenary and the aromatic substitution pattern and nature of substituting agents (electron donating or withdrawing). Sanguinarine forms the hydroxyl psuedobase in pH 7.4 water to a higher extent than Chelerythrine. Under basic aqueous conditions, the hydroxypsuedobase of Cheleryturine will dimerize forming an ether bridge between two Chelerythrine molecules attached to the carbon adjacent to the ring nitrogen. This ether is quite insoluble and does not convert readily to Chelerythrine in simulated gastric fluids due to low solubility. If the Chelerythrine dimer is placed in 0.1N HCL and then 30% methanol added, the conversion to Chelerythrine occurs rapidly.
The pseudoalcoholates (methoxy and ethoxy) of sanguinarine and chelerythrine are more potent antimicrobial agents than the parent alkaloids of these compounds. The methoxy, ethoxy and cyano sanguinarine psuedobases are about two times more potent than sanguinarine in antimicrobial assays. A crude mixture of chelerythrine methoxy and ethoxy pseudoalcoholates, also demonstrated improved efficacy over the parent in anti-microbial assays. It has been postulated that these pseudoalcoholates may act as prodrugs for their parent phenanthridinium alkaloid, however, this hypothesis is not general as the pseudoalcoholates (methanol and ethanol) of nitidine are less active in leukemia assays than the parent, nitidine. The lipophilic pseudobases are neutral, and more capable of passive diffusion across cell membranes and the blood/brain barrier than the parent alkaloid. Once inside the cell or the appropriate microenvironment in membranes it is likely that the pseudobase reverts to the parent benzo[c]phenanthridinium alkaloid resulting in increased potency and or safety. Polar pseudobase phenanthridines may be synthesized that offer activity to receptors, enzymes and cell types in the blood with greater selectivity than the parent phenanthridinium alkaloid. In certain instances prodrugs of active pharmaceutical agents have highly desirable properties. For example, prodrugs may provide superior efficacy and safety. Thus prodrugs of phenanthridinium alkaloids are highly desirable. The invention provides such compounds and also provides further advantages, which are described herein.